Project Summary Proliferative vitreoretinopathy (PVR) is a major complication of retinal detachments and is responsible for most of the failures in retinal reattachment surgeries. About 10% of retinal detachment patients suffer from PVR. These patients often have poor visual outcome despite multiple surgeries. Our previous work on inhibition of PVR has focused on pharmacological intervention concurrent with the retinal reattachment surgery. We have developed a porcine PVR model that provides a PVR-affected model eye with anatomical features comparable to human eye. Further, we ensure that the model is based on retinal injury and dispersion of retinal pigment epithelial (RPE) cells and not exogenous cells or proteolytic intervention as used in prior research. Our model is closest in pathophysiology to the human disease. For drug delivery, we have developed a novel intraocular aerosol generator (IAG), which generates a fine mist of drug solution at the tip of 25 gauge needle. IAG allows dispersing microgram quantities of a therapeutic agent on the retina in a gas-filled vitrectomized eye. In a pilot study, aerosolized delivery of 20 micrograms of an anti-proliferative agent, mitomycin C (MMC), has been shown to significantly lower the chances of PVR growth in our animal model. The present proposal is concerned with enhancement of the animal model so it would evolve into higher grades of PVR in a short time (2 weeks, instead of 8 weeks). The key to this improvement would be aspiration of RPE cells from the subretinal space and their subsequent injection to the outer retinal surface. Second generation of IAG will also be developed in this project to incorporate safety and control features that are essential for a device to be used in the operating room. Finally, a pre-clinical safety and efficacy study is proposed that would utilize cohorts of 20 pigs for each of 3 doses that are expected to cover the range of safe/efficacious to toxic dose. This Phase I project would lead to a roadmap for regulatory approval. We expect to have a pre-IND meeting with FDA at the end of this project, and conduct IND-enabling studies in Phase II project.